Mutational survivorship bias: The case of PNKP
| Autor: | Alejandro Leal, Gabriel Jimenez-Huezo, Andrés Arguedas, Luis Bermúdez-Guzmán |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Mutation rate
Heredity DNA Repair Protein Structure Prediction Survivorship medicine.disease_cause Biochemistry Homozygosity Database and Informatics Methods Protein structure 0302 clinical medicine Macromolecular Structure Analysis Genetics Mutation 0303 health sciences Crystallography Multidisciplinary Physics Condensed Matter Physics Phenotype Enzymes Mitochondria Nucleic acids DNA-Binding Proteins Phosphotransferases (Alcohol Group Acceptor) Survivorship bias Mitochondrial DNA repair Physical Sciences Crystal Structure Medicine Sequence Analysis Research Article Protein Structure Bioinformatics DNA repair Science Phosphatase Context (language use) Computational biology Biology Research and Analysis Methods 03 medical and health sciences Protein Domains medicine Solid State Physics Humans Amino Acid Sequence Molecular Biology 030304 developmental biology Cell Nucleus Phosphatases Biology and Life Sciences Proteins DNA Phosphoric Monoester Hydrolases DNA Repair Enzymes Protein kinase domain Enzymology Sequence Alignment 030217 neurology & neurosurgery Function (biology) DNA Damage |
| Zdroj: | PLoS ONE, Vol 15, Iss 12, p e0237682 (2020) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0237682 |
| Popis: | The molecular function of a protein relies on its structure. Understanding how mutations alter structure and function in multi-domain proteins, is key to elucidate how a pathological phenotype is generated. However, one may fall into the logical bias of assessing protein damage only based on the mutations that are viable (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with kinase and phosphatase function. Most mutations in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerance to disease causing mutations, we evaluated whether mutations in PNKP are under survivorship bias. Even when all mutations in the kinase domain are deleterious, we found a mayor mutation tolerability landscape in terms of survival. Instead, the phosphatase domain is less tolerant due to its low mutation rates, higher degree of sequence conservation, lower dN/dS ratios, and more disease-propensity hotspots. Thus, in multi-domain proteins, we propose the term “Wald’s domain” for those who are not apparently more associated with disease, but that are less resistant to mutations in terms of survival. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Thus, this bias should be taken into account when analyzing the mutational landscape in protein structure, function, and finally in disease. |
| Databáze: | OpenAIRE |
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